Ischemia, the restriction of blood supply to tissue, may result in tissue damage in a process known as ischemic cascade. Damage includes, but is not limited to, shortage of metabolic requirements (i.e., oxygen and glucose), build-up of metabolic waste products, inability to maintain cell membranes, mitochondrial damage, and eventual leakage of autolysing proteolytic enzymes into the cell and surrounding tissues. Brain ischemia may be chronic, e.g., leading to vascular dementia, or acute, e.g., causing a stroke. A stroke is the rapid decline of brain function due to a disturbance in the supply of blood to the brain caused by an obstruction or hemorrhage in a blood vessel. Obstructions encompass emboli, thrombi, and/or thromboemboli. An ischemic stroke is a stroke in which a blood vessel is restricted or occluded by an obstruction.
Ischemic stroke is the fourth leading cause of death in the United States, affecting over 795,000 patients per year and costing tens of billions of healthcare dollars. See, e.g., Dariush Mozaffarian et al., “Heart Disease and Stroke Statistics—2015 Update: A Report from the American Heart Association,” Circulation 2015; 131:e29-e322. Furthermore, patients who survive an ischemic stroke often require rehabilitation and management of symptoms including loss of brain function, motor skills, and memory. The extent of infarction (i.e., destruction of brain tissue) correlates with the extent of these lingering effects of the stroke and the mortality rate.
Of the existing treatment options for ischemic stroke, an older method, but still the primary method used in the United States, is to treat the clot with a clot-dissolving enzyme known as tissue plasminogen activator (“tPA”). The use of tPA has two primary drawbacks. First, tPA has limited effectiveness, in both dissolving clots and providing overall benefits for the patients. Many patients do not qualify for tPA treatment because they do not arrive at the hospital within the effective time window of approximately 4.5 hours after the onset of stroke. Even when used within that window, tPA achieves only a limited decrease in the overall mortality rate. Second, tPA may present adverse effects, such as serious internal bleeding. See, e.g., Götz Thomalla et al., “Two Tales: Hemorrhagic Transformation But Not Parenchymal Hemorrhage After Thrombolysis Is Related to Severity and Duration of Ischemia: MRI Study of Acute Stroke Patients Treated with Intravenous Tissue Plasminogen Activator Within 6 Hours,” 38(2) Stroke 313-18 (2007).
A newer method to treat ischemic stroke is mechanical thrombectomy, in which a device physically engages with a clot and is used to drag the clot out of the body. Usually, an operator, e.g., an interventional neuroradiologist or neurosurgeon, first establishes a path for the thrombectomy device to reach a clot in the cerebral vasculature by inserting an initial guidewire and guiding catheter into an artery in a lower region of the body, such as the femoral artery. Then, the operator steers the guidewire and guiding catheter to the skull base. The guidewire is removed and a combination of guidewire inside a microcatheter (optionally inside an intermediate catheter) is navigated through the guiding catheter and the arteries leading up to the obstruction and just past (i.e., distal to) the position of the obstruction or clot. Favoring whichever path poses least resistance, the guidewire passes either between the clot and the blood vessel wall or through the clot. The operator inserts a microcatheter over the initial guidewire to follow its path until reaching a position distal to the clot. The initial guidewire may be removed and replaced with a new guidewire (hereinafter “pushwire” to differentiate from an initial guidewire). This pushwire has a thrombectomy device attached to its distal end to engage with the obstruction and/or clot.
Currently, the most successful class of thrombectomy devices is based on neurovascular stent technology. Like stents, which are self-expandable and generally cylindrical, these devices tend to expand to the shape of the blood vessel walls. Thrombectomy devices may comprise thin metal struts arranged to create a cell pattern. During device expansion, a clot may become enmeshed in the cells and compressed against a blood vessel wall. At this point, blood flow may be partially or fully restored in the vessel, thus relieving ischemia.
Recently, the publication of the results of 5 landmark studies in the New England Journal of Medicine has shifted the paradigm of clinical management of ischemic stroke. The two-arm randomized trials, namely, “MR CLEAN”, “SWIFT PRIME”, “REVASCAT”, “ESCAPE” and “EXTEND-IA”, show that a combination of drug and device-based endovascular thrombectomy procedure is superior than a purely pharmacological approach. See, e.g., Jeffrey L. Saver et al., “Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke.” 372 New England Journal of Medicine 2285-2295 (2015). The studies have established a significant improvement in neurological outcomes in patients treated with tPA and strent retrievers compared to the group treated with tPA alone. These findings have spurred a wave of interest toward endovascular devices that can clear obstruction in the cerebrovasculature.
Aspiration, also called suction or thrombo-suction is a method used to dislodge obstructions and/or clot by navigating a cannula, such as a catheter, through the vessels of a patients, positioning the cannula in close proximity and/or contact with the obtruction, and applying a depression or vacuum through said cannula. When successful, the depression creates a force that moves the obstruction proximally and through the cannula and can be recuperated through the proximal end of said cannula. Aspiration can be used alone or in concert with a stentriver-based mechanical thrombectomy procedure.
One of the shortcomings of the aforementioned suction method is that the catheters currently used are smaller that the target arteries they are supposed to treat. Consequently, when the aspiration begins, part of the energy of the suction goes to the aspiration of fluid promial to the distal end of the catheter. In turn, the force created by the depression on the obstruction and/or clot is greatly reduced, so is the efficiency of suction of the obstructive material and complete recanalization of the artery.
Another shortcoming of the current suction method is that it often fails to prevent the dispersion of emboli in the vasculature. These emboli can, in turn, occlude distal and/or proximal branches of the cerebrovascular tree.
Another shortcoming of current mechanical thrombectomy and thrombo-suction devices and methods is reperfusion injury. Unfortunately, abrupt restoration of blood supply to ischemic tissues may cause reperfusion injury, which is additional damage to cerebral tissue, above and beyond damage caused by the ischemia itself. For example, reperfusion results in a sudden increase in tissue oxygenation, causing a greater production of free radicals and reactive oxygen species that damage cells. The restored blood flow also brings more calcium ions to the tissues causing calcium overloading that may result in potentially fatal cardiac arrhythmias and accelerated cellular self-destruction. Furthermore, reperfusion may exaggerate the inflammation response of damaged tissue, triggering white blood cells to destroy otherwise viable damaged cells.
Reperfusion injury is highly significant and can visibly increase the infarct size (i.e., destroyed tissue) by as much as 30%. See, e.g., Andrew Tsang et al., “Myocardial Postconditioning: Reperfusion Injury Revisited,” 289(1) Am. J. Physiol. Heart & Circ. Physiol. H2-7 (2005); Heng Zhao et al., “Interrupting Reperfusion as a Stroke Therapy: Ischemic Postconditioning Reduces Infarct Size After Focal Ischemia in Rats,” 26(9) J. Cereb. Blood Flow & Metab. 1114-21 (2006); Giuseppe Pignataro et al., “In Vivo and In Vitro Characterization of a Novel Neuroprotective Strategy for Stroke: Ischemic Postconditioning,” 28(2) J Cereb. Blood Flow & Metab. 232-41 (2008).
Existing thrombectomy devices and/or systems, including stent-based devices as well as thrombo-suction catheters, do not systematically or even adequately control the restoration of blood flow so as to minimize and/or prevent reperfusion injury. Thus far, the prevention of reperfusion injury has been limited to the field of interventional cardiology. During the management of an ischemic event in the heart, a cardiologist will treat the occlusion of a vessel with stents and/or balloon angioplasty to restore blood flow. Following reperfusion, a cardiologist may use an inflatable balloon to block and unblock blood flow through the vessel in intervals, thus modulating the resumed blood flow and minimizing reperfusion injury in a process called postconditioning.
Existing postconditioning devices and/or systems (e.g., catheters with high longitudinal rigidity and large diameters) are designed for the large arteries of the heart; however, the narrow and tortuous arteries of the cerebral vasculature render these existing devices and/or systems inadequate or at least less desirable in the context of ischemic stroke.
Existing postconditioning devices and/or systems also fail to incorporate simultaneous clot capture. In order to initiate reperfusion and perform postconditioning simultaneously, both a reperfusion member and flow modulation member must be disposed concurrently in the same region. Particularly in the brain, where space constraints make it difficult to fit both a reperfusion member and a flow modulation member, no existing postconditioning devices and/or systems are designed to simultaneously deploy a reperfusion member, such as a clot-capturing reperfusion member, and perform postconditioning for the ischemic tissue.
Thus, there remains a need for devices, systems, and methods designed to prevent, minimize, and/or treat ischemic stroke, and/or reduce and protect the cerebrovasculature from emboli dispersed during the treatment, and/or reperfusion injury by restoring and modulating blood flow in the cerebrovasculature.